managing orthostatic intolerance - sept 2010

Peter Rowe, MDJohns Hopkins University

School of Medicine

Moderated by Kim McClearyModerated by Kim McCleary

Managing Orthostatic Intolerance

September 1, 2010September 1, 2010

Hosted by Hosted by the CFIDS Association of Americathe CFIDS Association of America

Thank you for joining us!•• 13th CFIDS Association webinar of 2010 series13th CFIDS Association webinar of 2010 series

•• Dr. Rowe and Kim are in different locationsDr. Rowe and Kim are in different locations

•• 270 people preregistered to participate270 people preregistered to participate

•• Questions submitted with registration helped shape Questions submitted with registration helped shape discussion topicsdiscussion topics

•• Time for Q&A after presentation Time for Q&A after presentation ––

type them as you think of type them as you think of

themthem

•• Recording will be posted online within a couple of daysRecording will be posted online within a couple of days

•• Dr. Rowe is not able to address individualsDr. Rowe is not able to address individuals’’

questions about questions about

their symptoms, test results or therapytheir symptoms, test results or therapy

What we learned from registrants:

•• 50% have been diagnosed with orthostatic intolerance (OI)50% have been diagnosed with orthostatic intolerance (OI)

•• 30% have symptoms of OI but have not had testing30% have symptoms of OI but have not had testing

•• 60% indicate that OI has a significant impact on daily life60% indicate that OI has a significant impact on daily life

•• Only 5% indicate that it has little or no effectOnly 5% indicate that it has little or no effect

•• 60% have participated in another Association webinar60% have participated in another Association webinar

•• Lots of questions submitted in advance!Lots of questions submitted in advance!

Johns Hopkins University School of Johns Hopkins University School of MedicineMedicine

Baltimore, MarylandBaltimore, Maryland

Sunshine Natural Wellbeing Foundation Sunshine Natural Wellbeing Foundation Professor of Chronic Fatigue and Related Professor of Chronic Fatigue and Related DisordersDisorders

Specializes in pediatric and adolescent Specializes in pediatric and adolescent medicinemedicine

With colleague Hugh Calkins, credited with With colleague Hugh Calkins, credited with identifying link between CFS and OIidentifying link between CFS and OI

Peter M. Rowe, MD

CFIDS Association Webinar 1 September 2010

Peter C. Rowe, MD

Sunshine Natural Wellbeing Foundation Professor of Chronic Fatigue and Related Disorders

Johns Hopkins University School of MedicineBaltimore, USA

Introduction to the problem•

Definition and overview of the physiology

Common forms of OI in CFS•

Treatment of OI–

Non-pharmacologic measures

Treating contributory conditions–

Medications

15 year old with fatigue

Insidious onset of fatigue and lightheadedness at age 13Awakens unrefreshed after 10 hours of sleep. Tired all the time, worse by noon after being in school,

with shopping and any physical activityHeadaches, generalized achiness by school day’s endShoulders sore; worse low back and knee pain with

sittingConcentration off, easily distractedHome schooling due to fatigue in the last 18 months

15 year old with fatigue

Lightheaded every time he standsNo syncope, but some presyncopeSince onset of fatigue, craves salt: keeps salt

shaker in bedroom, licks it out of his handPMH: allergic rhinitis FH: 2 sibs, several maternal relatives flexible

Prior work-up:

WBC 6.6, Hgb 14.1, Plt 335Chemistry panel normalTSH 2.06 ESR 3, CRP < 1Urinalysis normalCardiac eval (with ECG and echo) normalBrain MRI normal

Mature, pleasant adolescent. Ht 50th %, Wt 75th %BP 120/80, HR 80 bpm General exam notable for: -Blue sclera-Beighton score 7/9-Subluxes shoulders at will

-5 0 5 15

StandingSupine Supine

51 bpm Δ

15 Year Old with Fatigue

Diagnoses:

Joint hypermobilityOrthostatic intolerance (POTS)(HR Δ

51 bpm [62 113])

Allergic rhinitis CFS

Treatment:

Fexofenadine 180 mg qD Fludrocortisone 0.1 mg dailyKCl 10 mEq qD

15 Year Old With CFS: Early Follow-up

Less congested•

Within a week of reaching the full 0.1 mg daily dose of fludrocortisone, noted improvement in all symptoms:

No LH, no HA, normal energy•

No post-exertional worsening of malaise

Wellness: 90s

Anxiety

Inhalant allergies/asthma

Infection

Pelvic vein incompetence

EDS/JHSDepression

Chiari type I or c-spine

stenosis

Chronic fatigue syndrome

Migraines

Orthostatic intolerance

Food allergies

Movement restrictions

Treatment of OI–

Medications

Orthostatic Intolerance

The term “orthostatic intolerance”

refers to a group of clinical conditions in which symptoms worsen with quiet upright posture and are ameliorated (although not necessarily abolished) by recumbency.

Modified from: Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol

2009;20:352-8.

Low PA

Rowell LB

Human Cardiovascular Control, 1993

Symptoms of Orthostatic Intolerance

Lightheadedness

DyspneaSyncope

Chest Discomfort

Diminished concentration PalpitationsHeadache TremulousnessBlurred vision

Anxiety

Fatigue

NauseaExercise intolerance Nocturia

Treatment of OI–

Medications

Illustrative case discussions

Common Forms Of Orthostatic Intolerance In Patients With CFS

Neurally mediated hypotension–

during orthostatic testing, 25 mm Hg drop in systolic BP, with no associated increase in HR

reproduction of typical orthostatic symptoms•

Postural tachycardia syndrome–

30 bpm increase in HR (or HR ≥

120) in the

first 10 minutes of orthostatic testing–

reproduction of typical orthostatic symptoms

pooling,↓

vasoconstriction ↓

intra-vascular volume

sympatho-adrenal response

NMH POTS

NE/Epi↓

NE/Epi

Standing/Tilt test

Neurally Mediated Hypotension

also known as

Vasovagal syncopeNeurocardiogenic syncopeVasodepressor syncopeNeurally mediated syncope

Neurally Mediated Hypotension

The most common cause of recurrent syncope•

More common in women, the young, those with low normal or low BP

Common following infection•

Family members often affected

Routine physical and lab tests normal•

Hypotension not detected unless orthostatic stress is prolonged

Fatigue common for hours after syncope

-4 -2 0 2 4 8 100

HR Δ 27 bpm

Catecholamines during upright tilt in syncope patients and controls

Benditt DG, Europace 2003;5:65-70.

Postural Tachycardia Syndrome (POTS)

Common disorder, F > M•

Insidious vs. onset after infection, surgery, trauma

Heterogeneous pathophysiology–

Hyperadrenergic and dysautonomic/neuropathic forms

Some classify into low-, normal-, and high-flow POTS–

Subsets with hypovolemia, elevated PRA/Aldosterone ratios, AChR ab positive, NET deficiency

Fatigue, exercise intolerance, palpitations common; often disabling symptoms

-5 0 5 15

HR Δ 66 bpm

Rosen & Cryer. Am J Med 1982;72:847-850

Dependent acrocyanosis

EDS/Joint hypermobility

CFSOrthostatic Intolerance

OI is strongly associated with CFS•

Upright posture aggravates CFS symptoms, often before HR/BP changes of POTS & NMH appear

Treatment of OI can improve CFS symptoms•

OI can be the primary abnormality, or it can be a consequence of a variety of other problems (e.g. deconditioning, an underlying infection)

Therefore, it is important to evaluate patients carefully for the non-cardiovascular problems

POTS and NMH can occur in the same person, and are not mutually exclusive

Treatment of POTS and NMH overlap

Insights on OI 1995-2010

Treatment of OI–

Medications

Illustrative case discussions

Step 1: Non-pharmacologic measures

Where possible, avoid factors that precipitate symptoms

Precipitating Factors For NMH & POTS

Increased pooling/decreased volume

Prolonged sitting or standingWarm environmentSodium depletionProlonged bed restVaricose veins High carbohydrate mealsDiuretics, vasodilators, alpha-blockersAlcohol

Precipitating Factors For NMH & POTS

Increased catecholamines StressExercisePainHypoglycemiaAlbuterolEpinephrine

Step 1: Non-pharmacologic measures•

Raising the head of the bed has an anti-diuretic effect and preserves blood volume at night

MacLean AR, Allen EV. Am Heart J 1944; 27:145

Compression garments–

Support hose (waist high > thigh high > knee high)

Body shaper garments–

Abdominal binders

Pilot data on the utility of compression garments

5 patients with CFS and OI were studied while taking their usual medications, with the exception of no beta-

blockers, stimulants, midodrine, pyridostigmine bromide on the day of the test.

Two 5-

minute standing tests were performed, in random order, separated by 15 minutes, one with a compression suit on, the other without.

Use postural counter-measures•

standing with legs crossed

squatting•

knee-chest sitting

leaning forward sitting•

elevate knees when sitting (foot rest)

clench fists when standing up[Use the muscles as a pump]

Courtesy Dr. A Smits

Fluids: Minimally 2 L per dayDrink at least every 2 hours Need access to fluids at schoolAvoid sleeping > 12 hrs/day

Increase according to tasteSupplement with salt tablets

Heart rate and BP responses to head-up tilt before (—) and after (----) intravenous saline

Burklow TR, et al. Neurally mediated cardiac syncope: autonomic modulation after normal saline infusion. JACC 1999;33:2059-66

Exercise

Avoid excessive bed rest/sleepingFor most impaired, start exercise slowly, increase graduallyRecumbent exercise may help at outset Manual forms of PT may be a bridge to better tolerance of exercise

[Inactivity is the enemy]

Treatment of Orthostatic Intolerance in CFS

Step 1: non pharmacologic measures

Step 2: treating contributory conditions

Step 3: medications–

Monotherapy

Rational polytherapy

Anxiety

Infection

EDS/JHSDepression

stenosis

Migraines

Food allergies

Treatment of Orthostatic Intolerance in CFS

Step 1: non pharmacologic measures

Step 2: treating contributory conditions

Step 3: medications–

Monotherapy

Rational polytherapy

pooling,↓

vasoconstriction ↓

intra-vascular volume

sympatho-adrenal response

NMH POTS

NE/Epi↓

NE/Epi

Standing

Vasoconstrictors Volume expanders

Reduce catecholamine release/effect

Therapy For Orthostatic Intolerance

blood volumeSodium (PO & occasionally IV), fludrocortisone, clonidine, OCPs

catecholamine release or effect β-blockers, disopyramide, SSRIs, ACE inh.

VasoconstrictionMidodrine, dexedrine, methylphenidate, SSRIs, SNRIs, aescin (horse chestnut seed extract); L-

DOPS (Droxidopa) in trials•

Misc: pyridostigmine bromide

Fludrocortisone

A synthetic mineralocorticoid used for several decades for the treatment of adrenal insufficiency and autonomic dysfunction

Promotes reabsorption of sodium in distal tubule•

Pharmacologic effects: volume expansion, improved small vessel response to catecholamines

Most common adverse effects: headache, swelling, hypertension, hypokalemia, depression

Usual dose: 0.1 mg daily; doses above 0.2 mg daily often associated with hypokalemia

Potassium chloride supplements recommended at initiation of therapy

Bou-Holaigah I, Rowe PC, Kan JS, Calkins H.JAMA 1995;274:96-7.

Fludrocortisone RCT design

Placebo

Fludro

Week 1 2 3 4 5 6 7 8 9 10 11

Assessments X X X

Off meds

Results: primary outcomes

Improvement Placebo

Fludro

Pin Wellness

5-point

.5210-point

15-point 10% 14% .7620-point

Mean change

2.7 (10.0) 3.8 (11.5)

Fludrocortisone Trial Limitations

Patients did not increase intake of sodium •

Fludrocortisone dose limited to 0.1 mg/d to avoid unmasking treatment assignment

Patients with prolonged CFS may respond differently; 71% in this study had CFS > 3 years

Insufficient power to exclude true improvements in young patients and those with CFS < 3 years

No patients < 18 enrolled•

No ability to account for “background noise”

of other

medical problems

Midodrine

Alpha-1 agonist vasoconstrictor; no CNS effect•

Duration of action only 4 hours

Common adverse effects: scalp tingling, paresthesias, piloerection, hypertension

Usual dose for adolescents/adults: –

2.5 mg q4h while awake for 3 days

Increase by 2.5 mg per dose q3-7 days until desired effect or to max of 10 mg per dose

dose OK if > 2 hours before bed; some need 10-15 mg/dose

Number of symptom free days during midodrine (treatment) or placebo study periods.

Ward C R et al. Heart 1998;79:45-49

10/16 vs. 2/16 normalHUT after 1 mo., andmore symptom free days (P< .0001)

Stimulants

Vasoconstrictors with CNS effects•

Dosing similar to that for ADHD

Most common adverse effects: insomnia, reduced appetite, moodiness, increased lightheadedness, agitation.

Usual dose for adolescents: –

Dextroamphetamine SR: start at 5 mg qAM, raise every 3-7 days by 5 mg as tolerated to 20-30 mg/day

Methylphenidate SR: start at 10 mg, increasing every 3- 7 days by 10 mg as tolerated to 30-50 mg/day

Stimulants: references

Susmano A, Volgman AS, Buckingham TA. Beneficial effects of dextro-amphetamine in the treatment of vasodepressor syncope. PACE 1993;16:1235-9.

Grubb BP, Kosinski D, Mouhaffel A, Pothoulakis A. Use of methylphenidate in the treatment of refractory neurocardiogenic syncope. PACE 1996;19:836-40.

Olson LG, Ambrogetti A, Sutherland DC. A pilot randomized controlled trial of dexamphetamine in patients with chronic fatigue syndrome. Psychosomatics 2003;44:38-43.

Blockmans D, Persoons P, van Houdenhove B, Bobbaers H. Does methylphenidate reduce the symptoms of chronic fatigue syndrome?

Am J Med 2006;119:167.e23-167.e30.

Beta blockers

Interfere with catecholamine-mediated increases in heart rate (for POTS) and force of heart contraction (to block initiation of NMH reflex)

May prevent epinephrine-induced vasodilation•

Most common adverse effects: fatigue, LH, decreased mood, cough/wheeze in asthmatics

Usual dose for adolescents: –

Atenolol 25 mg, increasing q3-7 days by 12.5 mg to 1 mg/kg (resting HR should be no lower than 50 bpm)

“Less is more”

(Raj S, Circulation, 2009)

Clonidine

Alpha-2 adrenergic receptor antagonist. Reduces sympathetic nervous system outflow; can lead to an expansion of blood volume in those with orthostatic intolerance.

Second line treatment for ADHD; can improve sleep when taken at night.

Most common side effects: worse fatigue and lightheadedness (due to the anti-hypertensive effect), and dry mouth. Must wean off slowly to avoid rebound hypertension.

Usual dose for

adolescents: 0.05 mg at night for 3- 7 days, then increase to 0.1 mg at night.

SSRI/SNRI

Inhibit the reuptake of serotonin (+/-

norepinephrine) at nerve terminals, leaving more serotonin (+/-

NE) available

as a neurotransmitter. •

Serotonin can have a vasoconstricting effect on blood vessels. One RCT shows efficacy for paroxetine in NMH.

Especially helpful in patients with co-morbid anxiety or depressed mood, or pain (duloxetine/Cymbalta)

Adverse effects: occasionally worse

lightheadedness or worse fatigue; bruising, sweating, reduced libido, diarrhea or nausea, or insomnia.

Increased risk of suicide in the early phase of treatment, lower risk of suicide later in those with severe depression

Pyridostigmine bromide

Acetylcholinesterase inhibitor•

Improves cardiovagal tone, lowering HR; other mechanisms may also play a role

Typical doses: –

Start with 30 mg twice/day-

three times/day

Increase gradually to 60 mg 2-3 times daily•

Adverse effects: usually well tolerated, but can cause nervousness, muscle cramps or twitching, nausea, vomiting, diarrhea, stomach cramps, increased saliva, anxiety, and watering eyes.

Pyridostigmine in OI(Singer W, et al. J Clin Neurophysiol, 2006:23;477-82)

How to select initial therapy?

Algorithm vs. individualized approaches

Johnson JN, et al. Pediatr Neurology 2010; 42:77-85

Individualized approach

SBP < 110:

fludrocortisone, midodrine

Increased HR at baseline or when upright:

β-blocker

Based on other clinical cluesIncreased salt appetite: fludrocortisone HA: β-blockerDysmenorrhea/worse fatigue with menses: OCP, DepoAnxiety/low mood: SSRI, SNRIMyalgias prominent: SNRIFH of ADHD: stimulantHypermobility: stimulant, midodrine

Modified from Bloomfield, Am J Cardiol 1999;84:33Q-39Q

Management of orthostatic intolerance

requires careful attention by the patient and the practitioner to the factors that provoke symptoms

requires a willingness to try several medications before a good fit is achieved

requires a realization that meds often can treat symptoms but do not necessarily cure OI

management of OI is one part of a comprehensive program of care

Association Between CFS, Orthostatic Intolerance and Ehlers-Danlos

Syndrome/Joint Hypermobility Syndrome

EDS/JH

Medical student with chronic fatigue

Onset of persistent fatigue, unrefreshing sleep, exercise intolerance, myalgias, cognitive difficulties at entry to SOM

PMH: onset of fatigue and syncope at age 11; initially averaged 2 episodes of syncope per yr, usually after standing or after showers

Frequent knee dislocations, 4 spont. pneumothoraces

LH several times/day; 2 episodes of presyncope/week

Typically with only 10-15 seconds of warning•

Worse fatigue after syncopal episodes

Symptoms thought due to atypical depression, although mood reported as OK. Worse syncope on sertraline 150 mg/day.

Had to repeat year 1

Tilt test

Baseline 74 112/70

NoneImmed tilt

115/75 LH, pale

SyncopeBrief sz.

Syncope resolved with increased salt, fluids, midodrine

Joint hypermobility and skin laxity noted•

Echo: aortic root normal, mild MVP

Dx: Ehlers-Danlos syndrome •

Persistent non-cyclic pelvic heaviness and low back pain with standing; concerned about ability to tolerate surgical clerkship

Pelvic Congestion Syndrome

Pelvic heaviness or pain with long periods of standing

Worse at end of the day, during menses•

Other symptoms: fatigue, dyspareunia, bladder urgency

Strong association with varicose ovarian veins

89% have > 80% relief after embolization of ovarian vein varicosities

Improved pelvic pain and orthostatic symptoms after embolization of ovarian vein varices

No further syncope•

Now able to stand for 7 hrs during surgical clerkship

Wants to be a surgeon

Anxiety

Infection

EDS/JHSDepression

stenosis

Migraines

Food allergies

Ehlers-Danlos Syndrome

Heterogeneous disorder of connective tissue•

Prevalence unknown, perhaps 1 per 5000

Characterized by varying degrees of:Skin hyperextensibilityJoint hypermobilityCutaneous scarring

Early varicose veins, easy bruising •

Easy fatigability and widespread pain common, of unclear etiology

Beighton score: On each side, 1 point for > 90o

hyperextensibility of 5th

finger, 1 point for thumb to forearm, and 1 for > 10o

hyperextensibility at elbow

Beighton score: on each side, 1 point for >10o

hyperextensibility at knees; 1 point for palms to floor

Hypermobility present if Beighton score is 4 or higher

CFS Associated With EDS and Orthostatic Intolerance

Among 100 adolescents in the CFS clinic at JHH over a 1 year period, we identified 12 with EDS (P < 0.01)6 classical-type, 6 hypermobile-type EDS

Rowe PC, Barron DF, Calkins H, Maumanee IH, Tong PY, Geraghty MT. J Pediatr 1999;135:494-9

EDS In CFS Patients With Orthostatic Intolerance

Fatigue present for median of 37 mo before EDS recognized (range 12-62)

5 had at least 3 episodes of syncope 7 had lightheadedness, but no syncopeNMH in 9/12, POTS in 10/12

Rowe PC, Barron DF, Calkins H, Maumanee IH, Tong PY, Geraghty MT. J Pediatr 1999;135:494-9

Joint Hypermobility In Children With CFS

Study question: do children with CFS have a higher prevalence of joint hypermobility? Beighton scores obtained in 58 new & 58 established CFS patients, and in 58 controlsMedian Beighton scores higher in CFS (4 vs. 1) Beighton score >

4 higher in CFS (60% vs. 24%)

Barron DF, Cohen BA, Geraghty MT, Violand R, Rowe PC. J Pediatr 2002;141:421-5

Beighton Joint Hypermobility Scores in 58 Adolescents With CFS And 58 Healthy Controls

0 - 1 2 - 3 4 - 5 6 - 7 8 - 9

HealthyCFS

Beighton scores

Barron, Geraghty, Cohen, Violand, Rowe. J Pediatr 2002;141:421-5

How Might Hypermobility Be Associated With OI and CFS?

Working hypothesis:

Connective tissue laxity in blood vessels allows increased vascular compliance, promotes excessive pooling during upright posture, leading to diminished blood return to the heart, and thus to OI symptoms

Rowe PC, et al. J Pediatr 1999;135:494-9

Dysautonomia in JHS

Subjects:–

48 consecutive patients with joint hypermobility syndrome referred to rheumatology division

30 healthy controls•

Methods–

Questionnaire of symptoms

Autonomic testing in a subsetGazit et al. Am J Med

2003;115:33-40

Dysautonomia in JHS: Results

Symptoms of OI more common in patients–

LH, syncope, palpitations, fatigue, impaired concentration, dyspnea, tremulousness, nocturia

OI more common–

78% of JHS vs. 10% of controls had OI

Standing tolerance 14.5 (6) vs. 19 (3.5) min, [P = .004]

Gazit et al. Am J Med 2003;115:33-40

Dysautonomia in JHS

Dose to increase HR 15 bpm

Dose to increase SBP 15 mm Hg

et al. Am J Med 2003;115:33-40

What are the risk factors for fatigue in JHS/EDS? 2.

What is the prevalence of OI in EDS patients?

What is the prevalence of CFS or fibromyalgia symptoms in JHS/EDS?

4. Do therapies directed at OI & related co- morbidities in JHS and EDS improve QOL?

Unanswered Questions

Upcoming Webinars:•• Thurs., Sept. 16: Thurs., Sept. 16: CFS & the Viral ConnectionCFS & the Viral Connection

Anthony L. Komaroff, MD, Harvard Medical SchoolAnthony L. Komaroff, MD, Harvard Medical School

•• Tues., Oct. 5: Tues., Oct. 5: Expanding ResearchExpanding ResearchSuzanne D. Vernon, PhD, CFIDS AssociationSuzanne D. Vernon, PhD, CFIDS Association

•• Thurs., Oct. 21: Thurs., Oct. 21: CoCo--Morbid Conditions Morbid Conditions ––

The The Alphabet Soup of CFSAlphabet Soup of CFS

Morris Papernik, MD, Hartford Hospital, Hartford, CT

For more information:•• CFIDS Association website: CFIDS Association website: www.cfids.orgwww.cfids.org•• Orthostatic intolerance: Orthostatic intolerance: http://http://www.cfids.org/aboutwww.cfids.org/about--cfids/orthostaticcfids/orthostatic--

intolerance.aspintolerance.asp

•• Medications for OI: Medications for OI: http://http://www.cfids.org/cfidslink/2009/070104.aspwww.cfids.org/cfidslink/2009/070104.asp•• Other therapies for OI: Other therapies for OI: http://http://www.cfids.org/cfidslink/2009/070105.aspwww.cfids.org/cfidslink/2009/070105.asp

•• Webinars:Webinars:

http://www.cfids.org/webinar/series2010.asphttp://www.cfids.org/webinar/series2010.asp•• SolveCFS BioBank:SolveCFS BioBank:

http://http://www.cfids.org/biobank/announcement.aspwww.cfids.org/biobank/announcement.asp•• CFIDSCFIDSLinkLink

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Our Mission:

For CFS to be widely understood, diagnosable, curable and preventable.

Our Strategy:

To stimulate research aimed at the early detection, objective diagnosis

and effective treatment of CFS through expanded public, private and commercial investment.

Our Core Values:

To lead with integrity, innovation and purpose.

managing orthostatic intolerance - sept 2010

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